Making antibodies act like enzymes.
By adding the catalytic virtues of enzymesto the binding abilities of antibodies, two teams of scientists say they have made the first catalytic antibodies. They say their work illustrates a powerful new strategy for designing sepcialized molecular tools for research in biology, chemical synthesis and medicine. Specific biomedical applications could someday include dissolving blood clots and cutting up viruses, they suggest.
Molecular biologists Alfonso Tramontano,Kim D. Janda and Richard A. Lerner of the Scripps Clinic and Research Foundation in La Jolla, Calif., and chemists Scott J. Pollack, Jeffrey W. Jacobs and Peter G. Schultz of the University of California at Berkeley performed the separate studies, described in the Dec. 19 SCIENCE. "This is the first real demonstration of catalytic antibodies," says Schultz.
Antibodies are nature's masters at recognizingand binding to specific molecular structures. Their biological responsibility is to advertise the presence of foreign, and often infectious, antigens in the blood and tissues so that antigen-eating macrophages or other complex immune mechanisms know where to go. Biological catalysts or enzymes are nature's experts at negotiating the occurrence's of specific chemical reactions within organisms. Without enzymes, many of these vital reactions would require temperatures or pH conditions that organisms cannot withstand.
Stanford University emeritus chemistryprofessor Linus Pauling suggested in 1948 that enzymes might be able to do such things by strongly binding to the reacting molecules, or substrates, in ways that favor midreaction "transition state" structures, which then quickly rearrange into the products of the reaction. Any factor that favors these transition states over other possible structures would increase the rate of the reaction.
The Scripps scientists reasoned that ifPauling's conjecture is correct, they might be able to make a chemical receptor, such as an antibody, that binds specifically to molecules that "look" like the theoretical transition states of an enzyme's specific substrate. "Then you could use that binding energy to do chemical work," Lerner says. According to this line of thought, appropriate antibodies might bind the actual substrate in such a way that they catalyze reactions normally executed by enzymes.
The Scripps grou psynthesized compoundscalled phosphonates esters, which resemble the biologically vital structures called carboxylic esters in their transition states as they undergo cleavage by water, or hydrolysis. The scientists injected the phosphonate esters into mice to elicit antibodies, which they hoped would not only bind to specific carboxylic esters but also enzymatically cleave or hydrolyze specific chemical bonds. After purifying and cloning the antibodies, the scientists found that they do hydrolyze carboxylic esters, but only if the esters have been chemically "activated," or destabilized, beforehand.
"We'd like to develop antibodies thatcatalyze substrates that don't require prior activation," says chemist E.T. Kaiser at Rockefeller University in New York City. "But it's really a good beginning to the whole problem of trying to develop catalytic antibodies."
The Berkeley trio used another tactic. Theyidentified existing antibodies that bind specifically to a compound that closely resembles the transition state of carbonate compounds, which also contain ester structures. Here, too, the antibodies bound only to molecules closely related to those compounds for which the antibodies were chosen, and the antibodies catalyzed hydrolysis reactions in the manner of enzymes.
"Lerner's work and my work show thatit can be done and that the idea of catalytic antibodies is viable," says Schultz. "But to really do it right and extend it to other systems you have to know how and why it's working."
So far the two groups have succeededin designing catalytic antibodies that perform one kind of reaction. But Lerner says he will be able to design enzymatic antbodies, or "abzymes," that perform a range of chemical job such as making and breaking specific bonds between the amino acids that make up proteins. "We're looking at a huge variety of reactions," says Shultz.
Lerner says this work could usher in a"new era" of discovering finer details about how enzymes work. The researchers say their work could lead to ways to obtaining enzymes tailor-made for just about any purpose a molecular biologist could dream up.
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|Date:||Dec 20, 1986|
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